ABSTRACT Preclinical Alzheimer?s disease (pre-AD) is a newly defined stage of AD reflecting current evidence that measurable biomarker changes in the brain may occur years before symptoms affecting memory, thinking or behavior can be detected. Current noninvasive and low-cost technologies/biomarkers for diagnosis of pre-AD are still being developed and not ready for use in general practice. Genetic studies have identified an association between the presence of apolipoprotein ?4 allele (APOE4) and the common form of AD. However, the APOE4 genotype alone is not a valuable biomarker for predicting AD because many without APOE4 will develop AD, and many with APOE4 will not. Neuroimaging studies using fMRI and PET have shown that cognitively normal APOE4 carriers develop cerebrovascular and metabolic alterations decades before any clinical symptoms occur. Thus, these early cerebral functional alterations may serve as sensitive biomarkers for assessment of pathological progress and therapeutic interventions for AD at early stage. Supported by an existing parent R21 award that is not currently focused on AD, we have developed a noninvasive, low-cost, wearable, near-infrared diffuse speckle contrast flow-oximetry (DSCFO) device for simultaneous measurements of cerebral blood flow (CBF), cerebral oxygen saturation (StO2), and cerebral oxidative metabolism (CMRO2) in newborn infants. In this supplement application, we propose to investigate DSCFO measurements of cerebrovascular and metabolic alterations as noninvasive and low-cost biomarkers for early diagnosis of pre-AD. We will conduct a randomized, controlled, single-blinded (investigator), biomarker validation trial of DSCFO measurements of cerebral hemodynamic and metabolic alterations throughout a novel Bluegrass memory task in cognitively normal older subjects (?65 yrs) with equal distributions of APOE4 carriers and noncarriers. Given its high temporal resolution and quantitative multi-parameter outputs, DSCFO is excellent for detecting dynamic alterations in cerebral hemodynamics and metabolism, which are strongly related to early cerebrovascular and neurological problems before developing AD and dementia. Thus, we expect that the patterns of brain functional responses to memory- induced tasks, quantified by DSCFO measurements of StO2, CBF, and CMRO2, will differ in APOE4 carriers and noncarriers. As subjects with AD generally suffer from multiple neurovascular problems, multiple functional parameters are expected to provide a more comprehensive assessment of neurovascular impairments than a single parameter alone. If successful, clinicians will have a low-cost, continuous, and wearable technology for continual and longitudinal monitoring of cerebral hemodynamics and metabolism, potentially obviating the extensive use of expensive and cumbersome technologies such as fMRI and PET. This pilot study would enable us to acquire preliminary data for the application of larger funds with longer durations (e.g., R01) to support validation of the noninvasive and low-cost optical biomarkers for screening, classification, and longitudinal monitoring of progression and interventions in AD with a focus on the preclinical stage.